A two-receptor pathway for catabolism of Clara cell secretory protein in the kidney.
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Clara cell secretory protein (CCSP) is a transport protein for lipophilic substances in bronchio-alveolar fluid, plasma, and uterine secretion. It acts as a carrier for steroid hormones and polychlorinated biphenyl metabolites. Previously, the existence of receptors for uptake of CCSP.ligand complexes into the renal proximal tubules had been suggested. Using surface plasmon resonance analysis, we demonstrate that CCSP binds to cubilin, a peripheral membrane protein on the surface of proximal tubular cells. Binding to cubilin results in uptake and lysosomal degradation of CCSP in cultured cells. Surprisingly, internalization of CCSP is blocked not only by cubilin antagonists but also by antibodies directed against megalin, an endocytic receptor that does not bind CCSP but associates with cubilin. Consistent with a role of both receptors in renal uptake of CCSP in vivo, patients deficient for cubilin or mice lacking megalin exhibit a defect in tubular uptake of the protein and excrete CCSP into the urine. These findings identify a cellular pathway consisting of a CCSP-binding protein (cubilin) and an endocytic coreceptor (megalin) responsible for tissue-specific uptake of CCSP and associated ligands. (+info)
Outbreak of Chinese herb nephropathy in Japan: are there any differences from Belgium?
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OBJECTIVE: The purpose of this article was to study and clarify the features of Chinese herb nephropathy (CHN) in Japan. PATIENTS AND METHODS: The subjects consisted of patients diagnosed as having CHN in Saiseikai Nakatsu Hospital and of those reported in the literature in Japan. We investigated the clinical and histological features of CHN patients in Japan and compared them with the Belgian cases. RESULTS: The remarkable differences were as follows: (1) high prevalence in males compared with Belgian cases, (2) Fanconi syndrome was found in most cases, (3) no patients had malignant tumors in the urinary tract. In addition, the ascribed Chinese medicines in Japan were divided into three groups: 'Tenshin-toki-shigyaku-ka-gosyuyu-syokyo-to', 'Boui-ougi-to', and others. CONCLUSION: CHN in Japan has some characteristics distinguished from Belgian nephropathy. One hypothesis is a susceptibility to aristolochic acids (AAs), which is considered to be a causative agent, may be different among races. Another is that there could be some other toxic substances affecting the clinical findings although they are not identified at present. Further studies must be undertaken to clarify these differences. (+info)
ARC syndrome: an expanding range of phenotypes.
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AIM: To describe the clinical phenotype in infants with ARC syndrome, the association of arthrogryposis, renal tubular acidosis, and cholestasis. METHODS: The medical records for six patients with ARC syndrome were reviewed, presenting over 10 years to three paediatric referral centres. RESULTS: All patients had the typical pattern of arthrogryposis. Renal Fanconi syndrome was present in all but one patient, who presented with nephrogenic diabetes insipidus. Although all patients had severe cholestasis, serum gamma glutamyltransferase values were normal. Many of our patients showed dysmorphic features or ichthyosis. All had recurrent febrile illnesses, diarrhoea, and failed to thrive. Blood films revealed abnormally large platelets. CONCLUSIONS: ARC syndrome exhibits notable clinical variability and may not be as rare as previously thought. The association of Fanconi syndrome, ichthyosis, dysmorphism, jaundice, and diarrhoea has previously been reported as a separate syndrome: our observations indicate that it is part of the ARC spectrum. (+info)
Glomerular protein sieving and implications for renal failure in Fanconi syndrome.
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BACKGROUND: Glomerular sieving coefficients (GSCs) of proteins have been measured extensively in animals but not humans. We have studied the proteinuria of Fanconi syndrome, a "knock-out" of renal tubular protein reabsorption, to estimate GSCs and detect potential contributors to development of renal failure. METHODS: Immunoassay of proteins and polypeptides in serum and urine of patients with early Dent's disease (mean GFR = 83 mL/min, range 60 to 101, N = 5), Lowe's syndrome (N = 3), and ADIF (N = 2) were used. RESULTS: Twenty-one proteins, ranging in mass from insulin (5.1 kD) and parathyroid hormone (PTH; 9.4 kD) to transferrin (78 kD) and intact IgG (160 kD), were present in Fanconi urine at> 6 to 1000-fold normal. A simple model assuming complete "knock-out" of the reuptake of each protein filtered normally by the glomerulus was applied to protein excretion by Dent's patients. GSCs were estimated for 12 plasma proteins, including albumin (7.7 +/- 0.9 x 10-5) and IgG (4.2 +/- 0.28 x 10-5; mean +/- SEM). We calculated the albumin concentration in normal glomerular filtrate to be 3.5 +/- 0.41 mg/L (53 +/- 6.4 nmol/L), consistent with studies in rat and dog. CONCLUSIONS: To our knowledge, this study provides the first estimates of human in vivo GSCs. Our model explains why tubular proteinuria of Fanconi syndrome includes proteins of mass of albumin and above as well as low-molecular-weight proteins, and further characterizes the endocytic pathway(s) believed defective in these syndromes. High urinary concentrations of potentially bioactive hormones such as PTH, insulin, IGF-1 and the chemokine monocyte chemoattractant protein-1 (MCP-1), were found; their presence in tubular fluid may contribute to the hypercalciuria, interstitial fibrosis, and the progressive renal failure of Fanconi syndromes. (+info)
Urinary megalin deficiency implicates abnormal tubular endocytic function in Fanconi syndrome.
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Normal reabsorption of glomerular filtrate proteins probably requires recycling of the endocytic receptors megalin (gp330) and cubilin. Both receptors are located on the luminal surface of the renal proximal tubule epithelium. Whether abnormal amounts of receptor are present in the urine of patients with Dent's disease, Lowe's syndrome, or autosomal dominant idiopathic Fanconi syndrome was explored. They are all forms of the renal Fanconi syndrome and are associated with tubular proteinuria. Urine samples of equal creatinine contents were dialyzed, lyophilized, and subjected to electrophoresis on nonreducing sodium dodecyl sulfate-5% polyacrylamide gels. Proteins were blotted and probed with anti-megalin IgG, anti-cubilin IgG, or receptor-associated protein. Megalin and cubilin levels detected by immunochemiluminescence were measured as integrated pixels and expressed as percentages of the normal mean values. A striking deficiency of urinary megalin, compared with normal individuals (n = 42), was observed for eight of nine families with Dent's disease (n = 10) and for the two families with Lowe's syndrome (n = 3). The family with autosomal dominant idiopathic Fanconi syndrome (n = 2) exhibited megalin levels within the normal range. The measured levels of cubilin were normal for all patients. These results are consistent with defective recycling of megalin to the apical cell surface of the proximal tubules and thus decreased loss into urine in Dent's disease and Lowe's syndrome. This defect would interfere with the normal endocytic function of megalin, result in losses of potential ligands into the urine, and produce tubular proteinuria. (+info)
Inhibition of Na(+)-dependent transporters in cystine-loaded human renal cells: electrophysiological studies on the Fanconi syndrome of cystinosis.
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Cystinosis is the most common cause of the renal Fanconi syndrome in children, leading to severe electrolyte disturbances and growth failure. A defective lysosomal transporter, cystinosin, results in intralysosomal accumulation of cystine. Loading cells with cystine dimethyl ester (CDME) is the only available model for this disease. This model was used to present electrophysiologic studies on immortalized human kidney epithelial (IHKE-1) cells that had been derived from the proximal tubule with the slow whole-cell patch clamp technique. Basal membrane voltages (V(m)) of IHKE-1 cells were -30.7 +/- 0.4 mV (n = 151). CDME concentration-dependently altered V(m) with an initial depolarization (2.7 +/- 0.2 mV;n = 76; 1 mM CDME) followed by a more pronounced hyperpolarization (-9.9 +/- 1.0 mV;n = 49). Three Na(+)-dependent transporters were examined. Alanine (1 mM) depolarized IHKE-1 cells by 17.6 +/- 0.7 mV (n = 59), and phosphate (1.8 mM) depolarized by 9.7 +/- 1.1 mV (n = 18). Acidification of IHKE-1 cells with propionate (20 mM) resulted in a depolarization of V(m) by 7.1 +/- 0.3 mV (n = 21) followed by a repolarization by 2.9 +/- 0.3 mV/min (n = 17), reflecting Na(+)/H(+)-exchanger activity. Acute addition of 1 mM CDME did not alter the alanine- and propionate-induced changes in V(m), but it reduced the phosphate-induced depolarization by 37 +/- 9% (n = 10). Incubation with 1 mM CDME reduced the activity of all three transporters. Depolarizations by alanine and phosphate and the repolarization after propionate were inhibited by 57 +/- 4% (n =30), 45 +/- 9% (n = 9), and 78 +/- 15% (n = 8), respectively. In conclusion, this study demonstrates that CDME acutely alters V(m) of IHKE-1 cells and that at least three Na(+)-dependent transporters are inhibited, the Na(+)-phosphate cotransporter most sensitively. This might suggest that phosphate depletion and dissipation of the Na(+)-gradient are involved in the development of the Fanconi syndrome of cystinosis. (+info)
Follow-up and treatment of adults with cystinosis in the Netherlands.
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BACKGROUND: Cystinosis is a rare autosomal recessive disease, caused by intracellular cystine accumulation due to a defect in the lysosomal cystine carrier. Treatment with cysteamine favours the transport of cystine out of the lysosomes, diminishes organ damage, and postpones the progression of renal failure. The extra-renal deposition of cystine continues after renal transplantation, leading to later complications. The objective of this study was to evaluate the follow-up, the occurrence of late complications, the social status, and the adequacy of cysteamine treatment in adult patients with cystinosis. METHODS: The medical histories of 10 adult cystinosis patients aged 19-36 years were studied. The impairment of thyroid function, central nervous system, endocrine pancreas, and ocular manifestations, as well as treatment with cysteamine were evaluated. RESULTS: Eight patients received in total 12 renal grafts, one patient was dialysed and one received conservative treatment for chronic renal failure. Extra-renal complications were noted in six patients, loss of visual acuity in four, hypothyroidism in three, diabetes mellitus in one, cerebral atrophy and epilepsy in one, and swallowing difficulties in two patients. Ophthalmic control was not performed in two patients, thyroid function was not controlled in two and glycaemia not controlled in two patients. Seven patients received 2100-4000 mg cysteamine per day in 2 (n=2), 3 (n=1), 4 (n=3), or 6 (n=1) doses. Cystine concentration in leukocytes was measured once or twice a year in eight patients and was within the recommended range only in three patients. CONCLUSION: A high rate of extra-renal complications in adults with nephropathic cystinosis was found. Optimizing the cysteamine therapy may attenuate these complications. Better communication between paediatric and 'adult's' nephrologists is needed to improve follow-up and treatment of grown-up cystinosis patients. (+info)
The Fanconi syndrome of cystinosis: insights into the pathophysiology.
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Cystinosis is a lysosomal storage disease, and is one of the most common causes of the Fanconi syndrome. In vitro studies of the cystine-loaded tubule provided insights into the pathophysiology of the proximal tubular defect. Proximal tubules loaded with cystine have a generalized proximal tubule transport defect characteristic of the Fanconi syndrome. The decrease in proximal tubular transport with cystine loading is due to a decrease in active transport. In cystine-loaded tubules the ATP production is severely compromised. The cystine-loaded tubule has a lower intracellular phosphate concentration than that of control tubules. This low intracellular phosphate concentration in cystine-loaded tubules likely plays an important role in maintaining intracellular ATP level. Preservation of intracellular phosphate at control levels prevents the decrease in intracellula, ATP and the proximal tubule respiratory dysfunction with cystine loading. (+info)